TPL-2 Regulates Macrophage Lipid Metabolism and M2 Differentiation to Control T(H)2-Mediated Immunopathology

Persistent T(H)2 cytokine responses following chronic helminth infections can often lead to the development of tissue pathology and fibrotic scarring. Despite a good understanding of the cellular mechanisms involved in fibrogenesis, there are very few therapeutic options available, highlighting a significant medical need and gap in our understanding of the molecular mechanisms of T(H)2-mediated immunopathology. In this study, we found that the Map3 kinase, TPL-2 (Map3k8; Cot) regulated T(H)2-mediated intestinal, hepatic and pulmonary immunopathology following Schistosoma mansoni infection or S. mansoni egg injection. Elevated inflammation, T(H)2 cell responses and exacerbated fibrosis in Map3k8 (–/–)mice was observed in mice with myeloid cell-specific (LysM) deletion of Map3k8, but not CD4 cell-specific deletion of Map3k8, indicating that TPL-2 regulated myeloid cell function to limit T(H)2-mediated immunopathology. Transcriptional and metabolic assays of Map3k8 (–/–)M2 macrophages identified that TPL-2 was required for lipolysis, M2 macrophage activation and the expression of a variety of genes involved in immuno-regulatory and pro-fibrotic pathways. Taken together this study identified that TPL-2 regulated T(H)2-mediated inflammation by supporting lipolysis and M2 macrophage activation, preventing T(H)2 cell expansion and downstream immunopathology and fibrosis.